Human Risk Assessment of Endocrine-Disrupting Chemicals Derived from Plastic Food Containers

Authors

  • Du Yeon Bang,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Minji Kyung,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Min Ji Kim,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Bu Young Jung,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Myung Chan Cho,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Seul Min Choi,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Young Woo Kim,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Seong Kwang Lim,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Duck Soo Lim,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • A Jin Won,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Seung Jun Kwack,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Youngkwan Lee,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Hyung Sik Kim,

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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  • Byung Mu Lee

    1. Authors Bang, Kyung, Kim, Jung, Cho, Choi, Kim, Lim, Lim and Lee are with Div. of Toxicology, Sungkyunkwan Univ., authors Won and Kim are with Pusan National Univ., author Kwack is with Changwon National Univ., and author Lee is with Dept. of Chemical Engineering, Sungkyunkwan Univ. Direact inquiries to authors Lee and Kim (E-mails: bmlee@skku.ac.kr/hkims@pusan.ac.kr).
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Abstract

Abstract:  In the manufacture of plastic containers, various materials such as additives (for example, plasticizers, stabilizers, antioxidants), polymers (for example, polystyrene [PS], polycarbonate [PC], polyvinyl chloride [PVC]) are widely used. Endocrine disrupting chemicals [EDCs] can migrate as residual monomers (for example, styrene for PS or bisphenol A [BPA] for PC) presented in polymers, as additives (for example, phthalates for PVC) used in polymer manufacturing, and/or as contaminants from the polymers depending on physicochemical conditions such as temperature, UV light, pH, microwave, and mechanical stress. Some phthalates (for example, DEHP, DBP), styrene, or bisphenol have been suspected to have endocrine disrupting effects, but human toxicological effects of these compounds are very controversial. For these reasons, a comprehensive review on toxicological and risk assessment studies for these chemicals (phthalates, BPA, and styrene) was carried out to evaluate their safety in humans. On the basis of exposure estimates for the these chemicals and reference doses (RfDs), we calculated hazard index (HI = chronic daily intake/tolerable daily intake [TDI] or RfD). A HI of less than 1 suggests an exposure lower than the safety limit of the chemicals. We showed that the HI values of these chemicals were lower then 1, but there are one or several exceptions for di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), di-isodecyl phthalate (DIDP), and di-n-octyl phthalate (DnOP; for example, exposure via infant formula, packaged lunch, total exposure), where estimated their HI values are higher than 1, which suggests an exposure higher than the safety limits of the chemicals. However, the HI of BPA was 0.001–0.26 (3.57–1000 times lower than its safety limit), and the HI for styrene was 0.276 (3.62 times lower than its safety limit). In this article, we focused on recent issues concerning the endocrine-disrupting chemicals (EDCs) derived from plastic food containers or packaging. This review suggests that the use of plastic food containers might not exceed human safe limits n general with respect to endocrine disruptors aside from the exceptions of the phthalates mentioned earlier.

Introduction

Synthetic resins and their products are used for various applications in almost every aspect of human life. Numerous materials such as polyethylene (PE), polypropylene (PP), polystyrene (PS), polyvinyl chloride (PVC), polyethylene terephthalate (PET), phenolic resin, melamine resin, polyester resin, and polycarbonate (PC) are used as major ingredients for the manufacture of plastic bottles, food containers, food packaging, cosmetics containers, appliances, packaging foam, plastic film, and microwavable packaging (Hopewell and others 2009; Petersen and Jensen 2010). Most of these plastics contain additional chemicals to bestow properties such as flame resistance, color, flexibility, and softness. It has been suggested that the use of plastic additives may pose some risk to the environment and human health and may contribute to a growing global waste management problem (Shaxson 2009; Thompson and others 2009). In this regard, synthetic resins associated with plastics have been a source of concern due to the possible presence of endocrine-disrupting chemicals (EDCs), particularly in Korea.

The concern over the safety of plastics has grown with a continued increase in plastic production. Globally, plastic production has increased nearly 10% every year since 1950. From 1.5 million metric tons in 1950, the total global production of plastics has grown to approximately 178 million tons in 2000 and 260 million tons in 2007 (The Compelling Facts About Plastics 2007, 2009). Of the 230 million tons of global synthetic resin produced in 2005 (JPIF 2007) the US contribution constituted 49.7 million tons, representing 21.6% of the world production. Other producing countries included China (21.4 million tons; 9.3%) and Korea (10.9 million tons; 4.7%). A worldwide annual production of plastics was estimated to be over 300 million tons in 2010 (Halden 2010). Both low-density polyethylene (LDPE) and high-density polyethylene (HDPE) belong to the PE family and are used mostly in the manufacture of plastic food containers. The pliability of PVC food wrap comes from plasticizers, which can vary from 3% to 80%, by weight (Sheftel 2000). In some plastics, phthalates may constitute up to 50% of the total PVC weight (van Wezel and others 2000). In 2003, the production of phthalates in the European Union (EU) was estimated to be 49000 tons of di-butyl phthalate (DBP) and 595000 tons of di-ethylhexyl phthalate (DEHP; Oehlemann and others 2008). Recently, phthalates have received a great deal of attention as major EDCs due to potential health concerns. Phthalates are also used as plasticizers to increase the flexibility of PVC in food contact materials. Since EDCs including phthalates can migrate into food from plastic food containers or packaging depending on physicochemical conditions such as temperature, UV light, pH, microwave, and mechanical stress for a sufficient period of time, safety concerns over food packaging have been raised (Petersen and Jensen 2010; Guo and others 2010). BPA is used to make PC food and beverage containers, the resin lining of metal cans, dental sealants, and as an additive in a wide array of other products (Vandenberg and others 2007). The estimated EU production of BPA was 1150000 tons in 2005 (Oehlmann and others 2008). The potential human health effects of BPA have been comprehensively reviewed (NTP-CERHR 2008).

According to a survey conducted by the Korea Food and Drug Administration (KFDA) on the use of various food containers and packaging materials, the most commonly used raw materials were synthetic resins (71.6%), followed by glass (10.6%), metal (10%), and paper (7.5%; KFDA 2007a, 2007b). The same survey reported that the synthetic resins used for plastic food containers, in descending order, were PE (34.2%), PET (15.2%), PP (11.5%), PC (7.1%), and PS (3.5%; Table 1). In Korea, use of PC has markedly decreased to 2% or less due to public concerns over BPA toxicity, although the safety of BPA is controversial (Kim and others 2007; Hunt and others 2009; Ranjit and others 2010). A survey conducted in Japan (JHOSPA 2006) at the same time found a similar pattern of use: synthetic resin (64.6%), glass (7.0%), metal (15.6%), and paper (12.6%), with the use of synthetic resins for plastic containers being PE (26.8%) > PET (13.8%) > PP (13.3%) > PS (5.6%). The extensive use of PE reflects its status as the most popular plastic ingredient in the world. Moreover, use of PE for food contact substances is increasing sharply due to its safety and convenience.

Table 1.  –Types of synthetic resins and materials used for the manufacture of food containers and packaging (Unit,%).
Packaging material type Glass Metal Paper Others Synthetic resins Total (%)
PE PET PP PS PC PVC Subtotal
  1. Abbreviations: PE = polyethylene; PET = polyethylene terephthalate; PP = polypropylene; PS = polystyrene; PC = polycarbonate; PVC = polyvinyl chloride

  2. References aKFDA (2007a, 2007b).

  3. b JHOSPA (2006).

Use of food packaging materials (%)Korea (2006)a10.610.0 7.50.334.215.211.53.57.10.171.6100
 Japan (2006)b 7.015.612.60.226.813.813.35.6others 5.164.6100

This report summarizes a safety evaluation of plastic food containers and carries out a comparative risk assessment for EDC-related plastic ingredients including phthalates, styrene, and BPA for the manufacture of food containers.

Endocrine Disrupting Chemicals in Plastic Food Containers

Risk assessment or risk management processes of EDCs have been well reviewed (DeRosa and others 1998; Choi and others 2004; Phillips and others 2008; Iavicoli and others 2009). In the manufacture of plastic food containers, phthalates such as DEHP, DBP, benzyl butyl phthalate (BBP), di-isonoyl phthalate (DINP), di-isodecyl phthalate (DIDP), and di-n-octyl phthalate (DnOP); bisphenol A (BPA); and styrene have been reported as suspected EDCs in humans. Results from animal experiments indicate that some phthalates such as DEHP and DBP may produce developmental disorders and reproductive toxicity as a result of endocrine disruption (Kavlock and others 2002a, 2002b; Fisher and others 2003; Borch and others 2004, 2005). Laboratory animal studies suggest that phthalates induce hormonal dysregulation resulting in increased incidence of reproductive malformations and reduced androgen-dependent organ weight (Gray and others 2000; Foster and others 2001; Koo and Lee 2005; Lee and Koo 2007). Recently, the cumulative effects of exposure to multiple phthalates have been considered in the assessment of human health risk. It has been reported that the mixture of DBP and DEHP increased the incidence of reproductive malformations, including epididymal agenesis, and reduced the androgen-dependent organ weights in a cumulative, dose-additive manner (Howdeshell and others 2007, 2008). These experiments demonstrate that individual phthalates with a similar mechanism of action can elicit cumulative, dose-additive effects on fetal testosterone production and pregnancy when administered as a mixture. There are some human data available on phthalates, although the potential risks of phthalate exposure have not been clearly proven in humans (Kamrin 2009). Recently, epidemiological, clinical, and experimental data suggest that male reproductive disorders such as infertility, reduced sperm motility, and decreased sperm count could be due to the effects of phthalates (Duty and others 2003; Duty and others 2005; Hauser and others 2006). However, reports of human health effects due to phthalate exposure are still limited and sometimes contradictory. In a Puerto Rican study, higher serum concentrations of several phthalates and its major metabolite were found in 28 (68% of the samples) girls with premature thelarche patients than in the controls without breast development (Colon and others 2000). They detected DEHP in only 14% of the control samples and the concentration of this phthalate was significantly lower than the levels in patients samples (Colon and others 2000). However, there was no significant difference in urinary concentrations of phthalate metabolites between the girls with precocious puberty and the controls, suggesting that phthalate exposure might not be associated with precocious puberty in females (Lomenick and others 2010). In Indian women with endometriosis, serum concentrations of DBP, BBP, DnOP, and DEHP were significantly higher than in the control group, which suggests that PEs may have an etiological association with endometriosis (Reddy and others 2006). Additionally, endometriotic women showed significantly higher plasma DEHP concentrations than the control groups, and 92.6% exhibited detectable DEHP or MEHP in the peritoneal fluid (Luisi and others 2006). Nevertheless, none of the above human studies found a direct causal relationship between phthalate exposure and human effects due to limitations such as small sample size and no consideration of other contributing risk factors for human effects. As shown in Tables 2 and 3, we summarized the toxicological characteristics and acceptable exposure limits of EDC-related plastic ingredients used to make food packaging materials. These chemicals are found in a wide variety of products including food containers, bottles, cups, dishes, and packaging wraps. Of the chemicals used for plastic food containers, phthalates are high production volume plasticizers, and many phthalates are lipophilic with high partition coefficients (Cousins and Mackay 2000; Sacan and others 2005). In Korea, DEHP has been banned from use in food packaging materials since 1989 (KFDA 1999). DEHP, BBP, and DBP have been banned from use in the manufacture of articles and toys for children since 2006 (KATS 2005), and BBP and DBP have been banned from use in the production of baby bottles since September 2007 (KFDA 2007a). The EU banned the use of 6 phthalates (DEHP, DBP, BBP, DINP, DIDP, and DnOP) in toys and children's products that might be placed in the mouth (EPC 2005). In 2008, the U.S. Consumer Product Safety Improvement Act (CPSIA) banned 6 phthalates in children's products (CPSIA 2008). The law permanently bans BBP, DBP, and DEHP from toys and child care products, and temporarily bans DIDP, DINP, and DnOP until a scientific board determines whether or not they are safe. Other countries, including Japan, Argentina, and Mexico, have also banned phthalates from children's toys. In addition, diethyl hexyl adipate (DEHA) has been banned from use in food packaging wraps in Korea since 2005 due to its endocrine-disrupting properties (KFDA 2005).

Table 2.  –Toxicological classification of endocrine-disrupting chemicals used in plastic ingredients.
Compound Carcinogenicity Mutagenicity Reproductive and developmental Response Ref.
  1. Abbreviations: N = not classified; += positive results; –= negative results; IARC = International Agency for Research on Cancer.

  2. Note: Group 2B, Possibly carcinogenic to humans; Group 3 and Group C, Not classifiable as to its carcinogenicity to humans; Group D, Probably not carcinogenic to humans, classified by IARC.

BPAN+, −+ Atkinson and Roy (1995)
     Pfeiffer and others (1997)
     Ivett and others (1989)
     Haworth and others (1983)
     Tyl and others (2006)
     NTP (1982a)
BBPGroup 3 (IARC),+ Lee and Koo (2007)
 Group C (U.S.EPA)   IARC (2011)
     Galloway and others (1987)
     Zeiger and others (1985)
     Valencia and others (1985)
     Wolfe and Layton (2003)
     Ema and others (1992)
     Piersma and others (2000)
     Tyl and others (2004)
     Kwack and others (2009)
DBPGroup D (U.S.EPA)+, −+ Lee and Koo (2007)
     Kim and others (2005)
     Galloway and others (1987)
     Zeiger and others (1985)
     Field and others (1993)
    Zhou and others (2010)
     Mylchreest and others (1998)
     Mylchreest and others (1999)
     Mylchreest and others (2000)
DEHPGroup 3 (IARC), B2(U.S.EPA)+, −+ Lee and Koo (2007)
     IARC (2011)
     Galloway and others (1987)
     Zeiger and others (1985)
     Lindahl-Kiessling and others (1989)
    Sato and others (1994)
    Gray and others (1999)
     Regnier and others (2004)
DEPGroup D (U.S.EPA)  IARC (2011)
    Galloway and others (1987)
   + Zeiger and others (1985)
    Field and others (1993)
    Ishidate and Odashima (1977)
    Lamb and others (1987)
DEHAGroup 3 (IARC),+, −+ Califonia EPA (2002)
 Group C (U.S.EPA)   Galloway and others (1987)
     NTP (1982b)
     Singh and others (1975)
     Dalgaard and others (2003)
DIDPN+ Barber and others (2000)
     Hazleton (1986)
    Exxon Biochemical
     Sciences (1997)
     Hushka and others (2001)
     Waterman and others (1999)
DINPN+ EFSA (2005a)
     Kwack and others (2009)
     Lee and Koo (2007)
     CSTEE (2001)
     Koizumi and others (2002)
    Exxon Biochemical Sciences (1996a)
    Exxon Biochemical Sciences (1996b)
     Nikiforov and others (1995)
StyreneGroup 2B (IARC)+, −+ IARC (2011)
     Kankaanpaa and others (1980)
     Katakura and others (2001)
     Chernoff and others (1990)
     Daston and others (1991)
Table 3.  –Acceptable exposure levels (RfD, TDI) of endocrine-disrupting chemicals (EDCs) in plastic ingredients.
Compound RfD (μg/kg/day) TDI (μg/kg/day) Ref.
  1. Abbreviations: ADI = acceptable daily intake; RfD = reference dose (oral for chronic exposure); TDI = tolerable daily intake (oral); DNEL = derived no effect level.

BPA 5050 IRIS (2011)
    EFSA (2006)
    ILSI (2000)
    Jobling and others (1995)
   KFDA (2008)
BBP200 200US EPA (2011b)
 500 (DNEL) 500 CSTEE (1998)
DBP10010 EFSA (2005c)
DEHP 2037 CSTEE (1998)
 50 EFSA (2005d)
DEP8005000SCTEE (1998)
    WHO (2003)
DEHA600 300SCF (1995)
DIDP 150 Ishidate and Odashima (1977)
  250 CSTEE (1998)
DINP120 (ADI) 150US EPA (2008)
    CSTEE (1998)
Styrene200 120US EPA (2008)

BPA has also been widely used for the lining of food cans and PC bottles. On October 18, 2008, the government of Canada announced that BPA might be hazardous to babies and began an assessment to determine whether a ban in products such as baby bottles should be undertaken. The proposed risk management approach for BPA was followed by a 60-d consultation period, and regulations were expected to come into effect in 2009 (Erler and Novak 2010). However, Health Canada recently reported that exposure to BPA through the consumption of jarred baby food products would be extremely low and the current dietary exposure to BPA through food packaging uses is not expected to pose a health risk to the consumer (Health Canada 2008, 2009; WRBM 2009). Recent reports also demonstrated that the potential human risk of BPA migrated from PC bottles or food contact containers was negligible (Lim and others 2009a, 2009b). In the meantime, due to the growing safety concerns surrounding BPA, alternative chemicals that can replace BPA have been investigated and BPA-free food containers with thermoresistant copolyesters are now being marketed (Moskala 2003). A total allowable concentration (TAC) of 100 μg/L BPA was proposed assuming that a 70-kg adult consumes 2 L of water each day and adopting the default 20% U.S. EPA drinking water relative source contribution (Willhite and others 2008). As the use of EDC-related plastic materials for the manufacture of plastic food containers decreased or even replaced by other non-EDC chemicals, the potential safety concerns for plastic food containers should lessen.

Styrene is an intermediate chemical that is widely used for various polymers and copolymers such as PS, styrene-acrylonitrile (SAN), acrylonitrile-butadiene styrene (ABS), styrene-butadiene rubber (SBR), and styrene-butadiene latexes (SBL). There has been little public concern over its widespread use, despite the fact that styrene (dimers and trimers) is another suspected preliminary EDC (Illinois EPA 1997) and a possible human carcinogen that has been classified as a Group 2B compound (IARC 2011). The estrogenic effects of styrene oligomers using in E-SCREEN and estrogen receptor (ER) binding assay have been reported (Soto and others 1995; Ohyama and others 2001). In contrast, styrene dimmers and styrene trimers did not show any binding affinity to ER, luciferase reporter gene assay in HeLa cells transfected with ER expression plasmid, and immature rat uterotrophic assay (Ohno and others 2003). No specific migration limit (SML) as regulatory limit has been set for monomeric styrene, although overall migration should not exceed 10 mg/dm2 for the final article (SFO 2009).

In general, the scientific evidence for the aforementioned EDCs has come mainly from in vitro and in vivo studies. Human risk assessment should be based on the weight of evidence (WOE), particularly human data. However, animal data can be used to estimate risks considering uncertainty when adequate human data are not available.

Migration of Endocrine Disrupting Chemicals in Plastic Food Containers

BPA is a main component of manufacture of PC plastic. There has been extensive scientific research to examine whether BPA can subsequently migrate from PC plastic and epoxy resin products. A recent study on BPA migration from plastic baby bottles shows that the migration levels of BPA into food is extremely low, and the estimated infantile dietary exposure is below the tolerable daily intake (TDI) of 50 μg/kg bw established by EFSA (2006). Cao and others (2010) demonstrated that BPA was detected in all of the corresponding soft drink products in cans. BPA was detected at low concentrations ranging from 0.081 to 0.54 μg/liter in all beer samples in cans, indicating that migration from can coatings is the likely source for BPA in canned products. Previous our study indicated that the migration levels of BPA were analyzed in food samples by high-performance liquid chromatography (HPLC) from PC bottles according to the normal condition such as heating with microwave, heating in a boiling water bath, or filling them with boiling hot water. The mean BPA levels from the bottles increased in a time-dependent manner, with the range of not detected (ND) to 2.5 ppb after heating for 60 min. However, none of the PC bottles released BPA at levels that exceed the recently established SML of 600 ppb established by European Union and KFDA (2008a, 2008b). Data suggest that the use of PC plastic bottles in our daily life is considered safe in Korea (Lim and others 2009a, 2009b).

Thomson and Grounds (2005) found levels of 10–29 μg/kg of BPA in 80 different samples of food cans of New Zealand. BPA concentrations between 29.9 μg/kg and 80 μg/kg were found in 20 samples of vegetable cans from Brazil, France, Spain, Turkey, and U.S.A. (Brotons and others 1995). Brede and others (2003) analyzed 12 different PC baby bottles both new and second hand from Norway using water as food simulant by solid phase extraction, followed by CG-MS analysis. They found bisphenols migration of 0.23 μg/L in the new baby bottles, 8.4 μg/L in bottles dishwashed 51 times, and 6.7 μg/L in bottles dishwashed 169 times. Cao and Corriveau (2008) found bisphenols in baby bottles purchased in Canada, ranging from 228 μg/kg to 521 μg/kg after warming them up to 70 °C for 6 d. Maragou and others (2008) found levels of bisphenols migration from 2.4 μg/kg to 14.3 μg/kg in 31 PC baby bottles purchased in Greece. Based on these studies, the concentrations of BPA were not exceed the limit of 0.6 mg BPA/kg accepted by the European Union (European Communities 1996). Guo and others (2010) analyzed six phthalates in orange juice packaged in PVC bottle by a HPLC. DEP and DEHP were detected in the orange juice without the other four phthalates. Concentrations would increase with the storage time and reach up to 0.385 μg/mL and 0.662 μg/mL, respectively, when the expiration date arrived. The level of DEHP was about 110 times higher than the limiting one in drink water (6 ppb) regulated by U.S. EPA. Results suggest that PVC plasticized by DEHP should not be used as the packaging material for orange juice.

The migration of phthalates into foodstuffs from plastic food containers has been reported. Guo and others (2010) demonstrated that DEP and DEHP were detected in orange juice packaged in PVC bottle by a HPLC and the concentrations increased with the storage time up to 0.385 μg/mL and 0.662 μg/mL, respectively. González-Castro and others (2011) measured phthalic-acid (PA), DBP, DEP, dioctyl-phthalate (DOP), and BPA in vegetable cans, baby bottles, and microwaveable containers from the Mexican market. These EDCs chemicals were detected in all samples, and PA and DOP in particular were the most commonly found, and maximum concentrations were 9.549 μg/kg and 0.664 μg/kg, respectively from a jalapeno peppers can. Bosnir and others (2003) investigated the level and rate of migration of phthalates into three model solutions (distilled water, 10% ethyl alcohol, and 3% acetic acid). The highest level of released phthalates was measured in distilled water (54.5 mg/kg), followed by 44.4 mg/kg in 3% acetic acid, and 32.3 mg/kg in 10% ethyl alcohol. A more recent study (Cacho and others 2012) determined the migration of phthalates (for example, DEP, DBP, BBP, DEHP) in vegetables in the form of plastic packed salads and canned greens. DEP, DBP, and DEHP were found to migrate from the bags to the simulant and were detected in vegetables at concentrations in the 8–51 ng/g range. Generally, the minor differences in plasticiser concentrations released from plastic containers could be observed in different experimental procedures and the most decisive factor was the country of origin of bottles (Schmid and others 2008).

In 2005, the European Food Safety Authority (EFSA 2005a, 2005b, 2005c) finalized its risk assessment for several of the phthalate plasticizers based on the human exposure levels from the foods. Although all findings of phthalates were associated with the use of plasticized PVC, the levels of phthalates released from plastic food containers would not present a hazard for human health as indicated above the study results.

Risk Assessment of EDCs Used in Plastic Ingredients

The schematic procedure for the human risk assessment of plastic ingredients (such as EDCs) is depicted in Figure 1. In general, the risk assessment procedure can be carried out in two ways: (1) risk assessment through the exposure assessment of specific environmental media such as food and water or (2) risk assessment through biomonitoring of EDCs in human samples (urine, blood, or tissues), which reflect total exposure to EDCs regardless of source or route of exposure. For example, risk assessment for EDCs in plastic food containers is based on the exposure scenario when the estimated daily intake (EDI) of each food item and the concentration of EDCs in the food are available. In the case of risk assessment using biomonitoring data, the assessment of human exposure to EDCs is possible when toxicokinetics information about the chronic exposure to a specific chemical is available for extrapolation or interpretation. To assess chemical risks for humans, several approaches can be applied depending on the carcinogenic or noncarcinogenic nature of the chemicals in question. For an assessment of the risk associated with EDCs (BPA, phthalates, and so on.) from the use of plastic food containers, estimation of human exposure to EDCs can be compared with acceptable exposure limits established by the European Food Safety Authority (EFSA) or the United States Environmental Protection Agency (U.S. EPA). The acceptable exposure levels of EDC-related plastic ingredients are summarized in Table 3. In general, EFSA determines a TDI as an acceptable or permissible exposure level for humans, and the U.S. EPA similarly uses a reference dose (RfD) as an acceptable oral dose. Current TDI and RfD values for BPA are each 50 (μg/kg/day) and are derived from body weight changes in two- and three-generation studies with mice and rats (Tyl and others 2002; EFSA 2008; U.S. EPA 2011).

Figure 1–.

A Schematic procedure for human risk assessment of plastic ingredients, endocrine-disrupting chemicals (EDCs). Abbreviations: RfD = reference dose; ADI = acceptable daily intake; TDI = tolerable daily intake; NOAEL = no observed adverse effect level; UF = uncertainty factor (default values employed based on interspecies [10] and inter-individual variation [10]).

The EFSA has allocated TDI values for DBP (10 μg/kg/day), DEHP (50 μg/kg/day), DIDP (150 μg/kg/day), and DINP (150 μg/kg/day) based on liver effects and developmental and reproductive toxicity (Table 3). The U.S. EPA has also established RfD for BPA (50 μg/kg/day), BBP (200 μg/kg/day), DBP (100 μg/kg/day), DEHP (20 μg/kg/day), DEP (800 μg/ kg/day), and DEHA (600 μg/kg/day) (Table 3).

Margin of safety (MOS) approach

The MOS approach is applicable for risk assessment of new and existing substances (EC 1996). To determine the MOS, data on the no observed adverse effect level (NOAEL in μg/kg body weight/day) and the estimated daily intake (EDI in μg/kg body weight/day) are provided by the ratio of the specified dose (NOAEL; obtained from animal data) to the level of human exposure (MOS = NOAEL ÷ EDI). NOAELs in mg/kg derived from animal studies can be converted to human equivalent doses (HEDs) in mg/kg based on body surface area and the application of HED for the estimation of MOS will be more appropriate to minimize species variation between humans and animals (FDA 2005; Reagan-Shaw and others 2008).

The risk posed to human health by exposure to phthalates, BPA, and styrene via air, water, and food can be assessed in this way (Figure 1). A MOS ≥100 is generally considered to indicate no risk, while a MOS <100 indicates that there may be a risk that needs to be regulated (Willhite and others 2008; IPCS 1990). As food is a major exposure source of phthalates (for example, DEHP, DBP) in consumer products, consumers may have very few opportunities to effectively reduce their exposure. However, food and beverage manufacturing companies can contribute to the reduction in consumer exposure by avoiding the use of phthalates in food packages (including adhesives, imprints) and in food processing equipment (Wormuth and others 2006; Dickson-Spillmann and others 2009). Although there have been some indications of adverse effects of plastic ingredients in humans exposed in the work place or natural environment (for example, air), the exposure levels of plastic ingredients using plastic food containers are so low that they do not appear to pose a health threat to humans (Kamrin 2009).

Hazard index (HI) calculation

To carry out a risk assessment for plastic ingredients (for example, EDCs), another popular approach for noncancer agents is the calculation of HI, employed in this study. Although the hazard index (HI) approach leads to a similar result as the margin of safety (MOS) approach, HI can be used when acceptable exposure limits (for example, tolerable daily intake [TDI; μg/kg body weight/day], acceptable daily intake [ADI], or RfD) are available. Most HI values {HI = (total EDI) ÷ (ADI, TDI, or RfD)} estimated from human exposure to plastic ingredients such as BBP, DEHA, DEP, DEHP, DBP, and BPA are far less than 1 (Tables 4 and 5), suggesting that these chemicals are consumed at safe amounts. One example is a DEHP retort-pouched baby food case that exhibited an HI of 1.068 in a study in which the TDI of several types of phthalates were estimated from packaged lunch, olive oil, butter, and retort-pouched baby foods (Tsumura and others 2002). Two other examples of DEHP showed HIs of 3.656 and 1.678, respectively for infants (0–12 mo old) and toddlers (1–3 y old) exposed to DEHP higher than the safe limit of 37 μg/kg b.w./day (Wormuth and others 2006; Table 4). In the case of DBP, HI values were estimated to be 1.48 and1.64 via exposure to DBP contaminated packaged lunch at heating condition (Chen and others 2008) and infant formula (Muller and others 2003), respectively (Table 4). In each case of DIDP or DINP, an estimated HI value was higher than 1 (1.4 or 1.44), suggesting an exposure to DIDP or DINP higher than the safe limit of 150 μg/kg b.w./day (Muller and others 2003).

Table 4.  –Estimated daily intake (EDI) and hazard index (HI) for bisphenol A, phthalates, and styrene in different age groups.
Compound (TDI μg/kg/day) Medium Population EDI (μg/kg body weight/day) NOAEL (μg/kg body weight/day) HI i Ref.
  1. Notes: Heating 1, microwaved in a ceramic bowl for 3 min with the food being covered with plastic wrap but keeping the plastic wrap from contacting the food. Heating 2, microwaved on a ceramic plate for 3 min with the plastic wrap always contacting the food (contact area of plastic wrap was 100 cm2).

  2. aBPA Estimated Daily Intake (EDI, μg/kg person/day) was calculated based on reference [GIHE 2001; KMHWA 2006] data.

  3. bBPA EDI (μg/kg person/day) was calculated based on references [KMHWA 2006; KFDA 1999] data.

  4. cDEHP EDI (μg/kg person/day) was calculated based on references [Tsumura and others 2002; GIHE 2001; KMHWA 2006] data.

  5. dDEHP EDI (μg/kg person/day) was calculated based on references[KMHWA 2006; DIHE 2002] data.

  6. eBased on the assumption of a daily breathing volume of 10 m3 at work or 20 m3 at home or in an urban environment.

  7. fBased on the upper value of 50 μg BPA/liter of infant formula.

  8. gBased on the typical value of 10 μg BPA/liter of infant formula.

  9. hP: percentile, iHI: EDI/TDI.

BPA (50)Packaged pork (PC)Adults (60 kg)ND-0.36 (control-microwave 9 min)−5000 [EFSA 2006]ND−0.007 Lim and others (2009a)
 Food contact materialsInfant2.42Reproductive & developmental0.048 US FDA (2008)
  Adult0.185 toxicity in mouse;0.004 
 Breast milk onlyInfant (3 mo)0.2 ↑Body weight0.004 EFSA (2006)
 Infant formula fed with glass or nonpolycarbonate (PC) bottleInfant (3 mo)2.3 ↑Weight of the uterus+cervix+vagina (UCV) [Tyl0.046 SCF (2002)
 Infant formula (PC bottle)Infant (3 mo)11f (4)g and others 2008]0.220 Sonnenschein and others (1995)
 Infant formula (PC) and commercial foods/beveragesInfant (6 mo)13f (8.3)g 0.260 
 2 kg commercial foods/beverages1.5 year-old child5.3 0.106 
 3 kg commercial foods/beveragesAdult1.5 0.030 
 Urinary excretion of bisphenol AGeneral population0.16 0.003 
  metabolitesGeneral population0.04 to 0.08 (95% CI) 0.008–0.016 
 4 food groups/ Korea20–29 y0.37a 0.007 GIHE (2001) KMHWA (2006)
  (canned foods (n = 14); carbonated30–49 y0.20a 0.004 
  drink, coffee, beer, corn)50–64 y0.11a 0.002 
  > 65 y0.02a 0.0004 
 6 food groups/ Korea1–2 y0.01b 0.0002 KMHWA (2006)
  (canned foods (n = 50); cola, cider,3–6 y0.03b 0.0006 KFDA (1999)
  coffee, tuna, spam corn)7–12 y0.06b 0.001 
  13–19 y0.08b 0.002 
  20–29 y0.09b 0.002 
  30–49 y0.06b 0.001 
  50–64 y0.01b 0.0002 
  > 65 y0.01b 0.0002 
BBP (200)Packaged lunch (400 g)Adults (60 kg)1.38 (Heating 1 & Heating 2)−20000; ↑serum FSH in the F00.007 Chen and others (2008)
 Olive oilAdults(50 kg)0.25 (One time intake 20g) parental males [EFSA 2005a]0.001 Jobling and others (1995)
 10 food groupsAdult (60 kg)0.1 (mean) 0.3 (high, 97.5 P) –50000;0.001/ 0.002 MAFF (1996)
 Total daily oral intake(main dietaryAdults1 Developmental toxicity in rats; ↓AGD0.005 Muller and others (2003)
  sources; root &leaf crops)1 to 6 y5.9 (F1, F2) [Tyl and others 2004]0.030 
  7 to 14 y2.4 0.012 
 Total exposure (5 consumerInfants (0–12 mo) 5.5kg0.76/7.56 0.004/0.038 Wormuth and others (2006)
  groups,food,air, water,consumerToddlers (1–3 y) 13kg0.31/3.67 0.002/0.018 
  products,household dust, toys)Children (4–10 y)0.06/1.24 0.0003/ 0.0062 
  Female adults (18–80 y)0.27/1.65 0.001/0.008 
  Male adults (18–80 y)0.31/1.89 0.002/0.009 
DBP (10)Packaged lunchAdults (60 kg)14.8 (Heating 1)−50000; teratogenicity,1.480 1.415 Chen and others (2008)
  (400 g)  14.15 (Heating 2) embryotoxicity and  
 Grape seed oilAdults(50 kg)0.96 (One-time intake 20g) maternal toxicity in rat0.096 Jobling and others (1995)
 29 different mealsAdults (70 kg)1.8–4.1 (mean) 10.2 (high P)h [EFSA 2005c]0.180–0.410 1.02 Petersen and Breindahl (2000)
 Total daily oral intake(main dietaryAdults1.6 0.160 Muller and others (2003)
  sources; root &leaf crops)1 to 6 y8.0 0.800 
  7 to 14 y3.5 0.350 
 Infant formulas<6 mo (5.5 kg, ingesting16.4 1.640 
   900 g/day of formulae)    
  >6 mo (8 kg, ingesting6.6 0.660 
   525 g/day of formulas)    
 Total (infant formulas and baby food)>6 mo7.9 0.790 
 Total exposure (5 consumer groups,Infants (0–12 mo) 5.5 kg1.57/ 5.58 0.157/0.558 Wormuth and others (2006)
  food, air, water, consumerToddlers (1–3 y) 13 kg0.68/2.62 0.068/0.262 
  products, household dust, toys.)Children (4–10 y)0.29/1.25 0.029/ 0.125 
  Female adults (18–80 y)0.41/1.45 0.041‵/ 0.145 
  Male adults (18–80 y)0.45/1.61 0.045/0.161 
DEP (5000)Packaged lunch (400 g)Adults (60 kg)1.44 (Heating 1) 0.93 (Heating 2)−750000; rat ↓growth rate ↑organ weights0.0003 0.0002 Chen and others (2008)
 Total exposure (5 consumer groups,Infants (0–12 mos) 5.5 kg3.48/19.74 0.001/ 0.004 Wormuth and others (2006)
  food, air, water, consumerToddlers (1–3 y) 13 kg1.49/8.31 0.0003/ 0.0017 
  products, household dust, toys.)Children (4–10 y)0.76/4.44 0.0002/ 0.0009 
  Female adults (18–80 y)1.43/64.93 0.0003/ 0.0130 
  Male adults (18–80 y)1.15/50.94 0.0002/ 0.0102 
DEHA (300)ButterAdults (50 kg)1.11−28000; fetal toxicity in rat0.004 Jobling and others (1995)
 Direct exposure from floor and wall coveringConsumers0.456 e [EFSA 2005f]0.002 Stuer-Lauridsen and others (2001)
DEHP (37)Packaged lunch (400 g)Adults (60 kg)23.37 (Heating 1) 34.11 (Heating 2)− 5000; testicular toxicity in rat; ↓testes weight, germ0.632 0.922 Chen and others (2008)
 Retort-pouched baby foodInfants (9 mo)39.53 (One-time intake 80 g) cell depletion [EFSA1.068 Jobling and others (1995)
 Leached tea (tea bag) ND (Water 0 °C)- 18.64 (Water 100 °C) 2005d][Wolfe and Layton 2003]0–0.504 GIHE (2001)
   ND–28.39 (Storage 0–24 d) 0–0.767 
 Foods and dietsAdults2.5 (mean)−37000.068 EFSA (2005d)
   5(high, 97.5 P)h [CSTEE 1998]0.135 MAFF (1996)
 Total daily oral intakeAdults4.5 0.122 Muller and others (2003)
  1 to 6 y26 0.703 
  7 to 14 y11 0.297 
 Infant formulas<6 mo (5.5 kg, ingesting 900 g/day of formulas)9.8 0.265 
  >6 mo (8 kg, ingesting 525 g/day of formulae)3.9 0.105 
 Total (infant formulas and baby food)>6 mo23.5 0.635 
 29 different mealsAdults (70 kg)2.7- 4.3 (mean) 15.7 (high P)h 0.073– 0.116 (mean) 0.424 (high) Petersen and Breindahl (2000)
 Total exposure (5 consumer groups,food,air,water, consumer products,house hold dust, toys.)Infants (0–12 mo) 5.5 kg16.16/135.28 0.437/3.656 Wormuth and others (2006)
  Toddlers (1–3 y) 13 kg6.31/62.10 0.171/1.678 
  Children (4–10 y)1.97/17.44 0.053/0.471 
  Female adults (18–80 y)2.54/14.71 0.069/0.398 
  Male adults (18–80 y)2.85/16.32 0.077/0.441 
 3 food groups (33 brands)/ (Korean cookies,20–29 y22.01c 0.595 GIHE (2001)
  jelly, barbecue sauce)30–49 y8.79c 0.238 
  50–64 y4.30c 0.116 
  > 65 y0.30c 0.008 
 3 food groups (n = 15)/ Korean snack, soy7–12 y2.57d 0.695 KMHWA (2006) DIHE (2002)
  sauce, laver)13–19 y2.64d 0.714 
  20–29 y3.69d 0.100 
  30–49 y3.59d 0.970 
  50–64 y3.31d 0.895 
  > 65 y2.76d 0.746 
DIDP (150)Total oral exposureAdults3−15000,oral in dogs, liver0.020 Muller and others (2003)
  Infants (6–12 mo)210 changes −33000; rats,1.4 
  Children (1–6 y)53 decrease of F2 offspring0.353 
  Children (7–14 y)7 survival [EFSA 2005b]0.047 
 Total exposure (5 consumerInfants (0–12 mo) 5.5kg1.43/8.99 0.010/0.060 Wormuth and others (2006)
  groups,food,air,water,consumerToddlers (1–3 y) 13 kg0.51/4.24 0.003/0.028 
  products,household dust, toys.)Children (4–10 y)0.03/0.47 0.0002/ 0.0031 
  Female adults (18–80 y)0.00/0.08 0/0.0005 
  Male adults (18–80 y)0.00/0.09 0/0.0006 
DINP (150)Total oral exposureAdults5−15000; proliferation related0.033 Muller and others (2003) Exxon Biomedical Sciences (1994)
  Infants (6–12 mo)216 chronic hepatic and renal effects in rat −500000 reproductive organs1.44 
  Children (1–6 y)63 in rats; hepatic changes, ↑incidence0.42 
  Children (7–14 y)10 of spongiosis, hepatitis, ↑liver and0.067 
 Total exposure (5 consumerInfants (0–12 mo) 5.5 kg21.98/135.02 kidney weights [EFSA 2005e]0.147/0.900 Wormuth and others (2006)
  groups,food,air,water,consumerToddlers (1–3 y) 13 kg7.07/67.19 0.047/0.448 
  products,household dust, toys.)Children (4–10 y)0.19/5.61 0.001/0.037 
  Female adults (18–80 y)0.00/0.26 0/0.002 
  Male adults (18–80 y)0.00/0.29 0/0.002 
Styrene (120)Total intake (air, indoor, drinking0–6 mo<0.66–<0.79−300000; oral gavage for prenatal<0.006- <0.007Luderer and others (2005)
  water,soil,food, not including cigarettes)7 mo–4 y<0.63–<0.79 developmental toxicity in rats<0.005–<0.007 
  5–11 y<0.41–<0.58 <0.003 -<0.005 
  12–19 y<0.25–<0.39 <0.002- <0.003 
  20–70 y<0.20–<0.33 <0.002–<0.003 
 Indoor airAdults (70 kg)0.09–14 0.001–0.117Luderer and others (2006)
 Polluted drinking water (2L/day) 0.03 0.0003 Fishbein (1992)
Table 5.  –Estimated daily intakes (EDIs) of bisphenol A (μg /kg body weight/day) and HI values for various food samples.
Exposure source Population Condition EDI (μg/kg body weight/ day) HI e Ref.
  1. a,cBased on upper values of 50 μg bisphenol A/L of infant formula.

  2. b,d Based on typical values of 10 μg BPA/L of infant formula.

  3. e HI = Intake/RfD of BPA (50 μg/kg bw).

FormulaInfant4.5 kg bw, 700 mL canned formula at 6.6 μg/L BPA10.02 NTP (2007)
 6–11 mo/malesFormula-fed0.180.004 
 3 moFormula fed with glass or non-PC bottle2.30.05 EFSA (2006)
 3 moFormula fed with PC bottle11a/4b0.22/0.08 
 6 moFormula fed with PC bottle & commercial foods/beverages13c/8.3d0.26/ 0.17 
 0–4 mo0.7 L/day1.60.032 GIHE (2001)
 6–12 mo0.7 L/day0.80.016 
Breast milkInfant4.5 kg bw, 700mL canned formula at 6.3 μg/L10.02 NTP (2007)
 6–11mo/malesBreast-fed0.160.003 EFSA (2006)
 3 moBreast milk only0.20.004 
Aggregate ingestion1–6 yTotal (air,water,canned food1.20.024 Miyamoto and Kotake
 7–14 y & drink, tableware)0.550.011  (2006)
 15–19 y 0.360.007 
 >19 y 0.430.009 
Canned food6–12 mo0.38 kg/day0.850.017 SCF (2002)
 4–6 y1.05 kg/day1.20.024 SCF (2002)
 1–6 yFood items of 13 group (grain0.380.008 Miyamoto and Kotake
 7–14 y crops, fruits, vegetable and0.210.004  (2006)
 15–19 y so on)0.200.004 
 >19 y 0.290.006 
 Adults3 kg commercial food/beverages1.50.03 EFSA (2006)
  1.05 kg/day0.370.007 SCF (2002)
 Pregnant womenFish, juice &meat (18–46 y in southern Spain)1.1 (mean)0.022 Mariscal-Arcas and others (2009)
WineAdults0.75 L/day0.110.002 SCF (2002)
Baby food1.5 y2 kg commercial food/beverages5.30.11 EFSA (2006)
Canned foodAdultsFood items of 7 group (meats, fruits, vegetable, coffee and so on)1.5090.03 Lim and others (2009)
Aggregate ingestion1–4 yTotal (canned food, migration0.27–2.270.005–0.045 EWG (2007)
 5–11 y from polycarbonate bottles0.17–1.450.003–0.029Le and others (2008)
 12–19 y and all environmental0.10–0.800.002–0.016 
 Adults media)0.08–0.670.002–0.013 
      

These data suggest that estimated HI values are generally less than 1, suggesting exposure to levels lower than TDI, ADI, or RfD, but there are several exceptional cases of HI values >1 for phthalates (DEHP, DBP, DIDP, DINP), suggesting exposure to levels higher than the safe limits.

Table 5 summarizes the EDIs of BPA from various food samples. The data illustrate that, although infants and babies can be highly exposed to BPA via the consumption of formula, canned food, baby food, and breast milk (NTP 2007), the exposure levels are considered safe because HI values ranged from 0.002 to 0.26. In adults, the major exposure sources of BPA are canned beverages and wine (EFSA 2006), but HI values ranged from 0.002 to 0.03, indicative of safety. In addition, estimates of exposure to phthalates based on the measurement of urinary metabolites has demonstrated that human exposure levels of phthalates as measured by TDI for each phthalate ranged from 1.1% (BBP, mainly those >20 y of age) to 72.79% (DEHP, mainly those 6–11 y of age), which were all within the safe range (Table 6). It should be noted that both MOS and HI values need to be interpreted carefully as there is much uncertainty in the process of risk assessment. The possible sources of the uncertainties for the estimation of MOS or HI may be associated with the use of inaccurate or incomplete exposure data with analytical errors or the lack of analytical method validation, and the conversion of animal doses (for example, NOAELs) to the HEDs.

Table 6.  –Estimated daily exposure to phthalates (from urinary metabolite concentrations in comparison with TDI).
Compound (TDI, μg/kg body weight/day) Exposure level (μg/kg body weight/day) TDI (%) (95th P)* Age (year) Sampling year N Country Ref.
Median (95th P)*
  1. aValues for women aged 20–40 y of age in boldface; remaining values are for the rest of population.

  2. *95th P = 95th percentile.

BBP (200)0.73.31.6520–601988–1994289U.S.A. NCEH (2005)
 1.26.53.256–112001/2002392U.S.A. David (2000)
 0.42.21.1>2020011638U.S.A. Teitelbaum and others (2008)
 1.29.64.86–10200435U.S.A. 
 0.62.51.257–63200285Germany Koch and others (2003, 2007)
 0.42.81.42–142001/2002239Germany 
DBP (100)1.35.35.320–602001/2002392U.S.A. NCEH 2005
 0.62.62.66–1120011638U.S.A. Teitelbaum and others (2008)
 1.96.06.06–10200435U.S.A. 
 4.917.817.82–142001/2002239Germany Koch and others (2007)
DEP (5000)13901.1320–401988–1994192aU.S.A. Blount and others (2000)
 111301.6320–40 97 (woman)U.S.A. Kohn and others (2000)
 0.63.18.3820–601988–1994289U.S.A. NCEH (2005)
 3.82464.866–112001/2002392U.S.A. David (2000)
 1.71540.54>2020011638U.S.A. 
DEHP (37)4.51951.353–142001/2002254Germany Becker and others (2004)
 6.41232.432–7200336Germany Koch and others (2004)
 3.25.715.4120–59200319Germany Wittassek and others (2007)
 2.78.222.1612–142001/200253Germany Koo and Lee (2005)
 6.037.2100.5411–122003150Korea 
 21.4158.4428.1120–732003150 (woman)Korea 

Epidemiological Evidence of Phthalates, BPA, and PVC

Previous studies have demonstrated that BPA and phthalates are commonly found in foods. Although these compounds have relatively short half-lives in humans, they have been associated with a number of human health problems, including infertility, testicular dysgenesis, premature breast development, and recurrent miscarriage (Table 7) (Lang and others 2008; Sugiura-Ogasawara and others 2005; Tyl and others 2008; Colón and others 2000; Frederiksen and others 2011). A cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States was carried out using data from the 2003 to 2004 National Health and Nutrition Examination Survey (NHANES). Of the 1455 participants (18–74 y), higher urinary BPA concentrations were associated with an increased prevalence of diabetes (OR 1.39; 95% CI 1.21–1.60; P= 0.001; Lang and others 2008). Nonetheless, the authors suggested that independent replication and follow-up studies are needed to confirm these findings and to provide evidence as to whether the associations are causal. In another study, serum BPA concentrations were measured in 45 patients with a history of 3 or more consecutive first-trimester miscarriages and in 32 control healthy women with no history of miscarriages and infertility (Sugiura-Ogasawara and others 2005). The study results implicated high serum BPA concentrations with the presence of antinuclear antibodies, but not with hypothyroidism, hyperprolactinaemia, luteal phase defects, natural killer cell activity, or antiphospholipid antibodies, suggesting that BPA exposure might be associated with recurrent miscarriages. However, the causal relationship between BPA and miscarriages was not conclusive because other probable risk factors for miscarriage were not included for a comprehensive analysis.

Table 7.  –Epidemiological or human study results of bisphenol A, phthalate esters, plastics, and PVC.
Compound Study population Study method Results Ref.
  1. Abbreviations: AOR = adjusted OR; aPLs = antiphospholipid antibodies; ANAs = antinuclear antibodies; NK = natural killer cell.

BPA42 epoxy resin sprayers & 42 unexposed workersUrinary BPA (by HPLC)↓FSH(follicle-stimulating hormone) level Hanaoka and others (2002)
 1455 adults (18 -74 y) general population (U.S.)Urinary BPA and creatinine concentrations (Cross-sectional analysis)Diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% CI, 1.21–1.60; P < 0.001) Lang and others (2008)
   – Cardiovascular diagnosis (1.39; 95% confidence interval [CI], 1.18–1.63; P = 0.001) 
 22 renal disease predialysis patients &15 patients receiving hemodialysisBPA concentration in the sera– BPA accumulation affects the endocrine or metabolic system of the human body Murakami and others (2007)
 45 patients with a history of three or more (3–11) consecutive first-trimester miscarriages and 32 healthy womenSerum BPA, aPLs, ANAs, NK) activity, prolactin, progesterone, TSH and free T4Exposure to BPA associated with recurrent miscarriage Sugiura-Ogasawara and others (2005)
PVCCase-control study, 148 cases of testicular cancer and 314 healthy controlsInformation on lifetime working histories and specific exposuresSix-fold increase in the risk for seminoma (a type of testicular cancer). Plastic workers exposed to PVC Ohlson and Hardell (2000)
Phthalates (DEHP, DBP and so on)134 boys, 2–36 moAnogenital distance (AGD) & nine phthalate monoester metabolites↓Anogenital distance (AGD) among male infants with prenatal phthalate exposure Swan and others (2005)
 261 Korean children, age 8–11 yA cross-sectional study; urinary phthalate conc., of ADHD symptoms & neuropsychological dysfunction– Strong positive association between phthalate metabolites in urine and symptoms of ADHD among school-age children; ADHD scores significantly associated with DEHP metabolites but not with DBP. Kim and others (2009)
 41 thelarche patients and 35 controls for Puerto Rican girlsBlood serum analysis of phthalates by GC/MS– Premature breast development in a human female population (multifold higher serum phthalate concentration in patients as compared to controls) Colon and others (2000)
MBP and MEP289 participants in the Third National Health & Nutrition Examination Survey (NHANES III)Urinary phthalate and pulmonary function– MBP & MEP may be associated with adverse pulmonary function among adult men Hoppin and others (2004)
PlasticsDynamic cohorts of economically active 27445 women and 93665 menDanish occupational Hospitalization Register, from 1995 to 2005↑Incidence of infertility among women working, in the plastics industry, relative risk 1.23 (95% CI:1.01–1.48) Tyl and others (2004)
StyreneStyrene-butadiene rubber plants (n= 6); 1943–91; 13130 men; one year; vital status known for >99%, death certificates for 98% of the decedentsWithin-cohort comparison; the cohort follow-up reported– Leukemia (death certificates and medical records identified workers with leukemia between exposure to 1,3-butadiene, styrene, and dimethyldithiocarbamate) Delzell and others (2001) Sathiakumar and others (1998)
 Cytogenetic study;18 male workers exposed to styrene, 18 male controlsBlood and urine sample, lymphocyte cultures for cytogenetic examinations– Chromosomal aberrations were significantly higher in the workers Anwar and Shamy (1995)
   (6.06 ± 4.41) compared with controls 
   (3.44 ± 2.28) (P < 0.05) 

An examination of the Danish Occupational Hospitalization Register between 1995 and 2005 revealed that increased incidence of infertility was observed among women working in the plastics industry (Hougaard and others 2009). This study showed that, among female plastic workers, 107 cases of treatment for female infertility were observed compared to an expected 87.15 cases (relative risk [RR] 1.23 [95% CI: 1.01–1.48]). For male workers, the numbers were 41 and 49.9 cases, respectively with RR being 0.82 (95% CI 0.59–1.11). These data suggest that exposure to chemicals generated from the plastics industry may be weakly associated with female infertility, but not with male infertility. A Puerto Rican study demonstrated a possible association between exposure to phthalates and premature breast development in a human female population (Colón and others 2000). Danish children are exposed simultaneously to multiple phthalates. The highest exposure levels were found for DBP and DEHP, which in animal models are the most potent known antiandrogenic phthalates. The combined exposure to the isoforms of DBP, which have similar endocrine-disrupting potencies in animal models, exceeded the TDI for DnBP in several of the younger children (Frederiksen and others 2011).

Conclusion

Numerous plastic ingredients have been used for the manufacture of consumer products and human safety concerns regarding their use in plastic food containers have been raised. Although the use of synthetic resins may differ from country to country, the major synthetic resins used for plastic containers in Korea are: PE (34.2%) > PET (15.2%) > PP (11.5%) > PC (7.1%) > PS (3.5%), which is a pattern similar to that in Japan (Table 1). In terms of toxicological evaluation, PE, PET, and PP, which constitute the major synthetic resins used in plastic food containers, are non-EDC-related ingredients and are generally considered safe. Of the other minor EDC-related ingredients such as phthalates, styrene, and BPA, DEHP has been banned for use in food containers since 1989 in Korea, and BPA is now being replaced by a new copolyester. Nonetheless, the comparative risk assessment carried out in this study demonstrates that human exposure levels of phthalates, styrene, or BPA via various routes of exposure are far below acceptable exposure limits and fall within the safe range, except for some cases of DEHP, DBP, DIDP, and DINP that migrated from retort-pouched baby food, infant formulas, and package lunch.

In conclusion, synthetic resins used for the manufacture of plastic food containers are mostly non-EDC ingredients, and should be considered safe. The EDC-related ingredients in plastic containers include phthalates, styrene, and BPA, but their migration levels are mostly within the safe limits and HI values are less than 1, suggesting exposure lower than TDI, ADI, or RfD. However, there are some cases of HI values greater than 1 for phthalates (DEHP, DBP, DIDP, DINP), which needs a further evaluation of monitoring and risk assessment. In addition, a well-controlled follow-up study is required to better understand the human health risks associated with the use of plastics and plastic ingredients.

Abbreviations 

ABS

Acrylonitrile-butadiene styrene copolymer

ADI

Allowable daily intake

BPA

Bisphenol A

BBP

enzyl butyl phthalate

DBP

Dibutyl phthalate

DEHP

Di(2-ethylhexyl) phthalate

DINP

Di-isonoyl phthalate

DIDP

Di-isodecyl phthalate

DnOP

Di-n-octyl phthalate

EDC

Endocrine disrupting chemicals

FDA

Food and drug administration

HDPE

High-density polyethylene

HED

Human equivalent dose

HI

Hazard index

ILSI

International Life Sciences Institute

KFDA

Korea food and drug administration

LDPE

Low-density polyethylene

LLDPE

Linear low-density polyethylene

MOS

Margin of safety

NOAEL

No observed adverse effect level

PC

Polycarbonate

PE

Polyethylene

PET

Polyethylene terephthalate

PP

Polypropylene

PS

Polystyrene

PVC

Polyvinyl chloride

RfD

Reference dose

SAN

Styrene-acrylonitrile copolymer

SBR

Styrene-butadiene rubber

SBL

Styrene-butadiene latexes

SML

Specific migration limit

TAC

Total allowable concentration

TDI

Tolerable daily intake

U.S. EPA

U.S. environmental protection agency

VLDPE

Very-low-density polyethylene

WHO

World health organization

WOE

Weight of evidence

Acknowledgments

This study was supported by grants from KFDA, National Institute of Food and Drug Safety Evaluation (NiFDS), and National Research Foundation (NRF) of Korea (No.20090083538).

Conflicts of Interest

The authors have declared no conflict of interest.

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